The CFTR protein, or “cystic fibrosis transmembrane conductance regulator” protein, is a transmembrane protein brought to light during research on the gene responsible for cystic fibrosis (or mucoviscidosis). The CFTR channel appears to be one of the keys to the regulation of chloride ion transport in epithelial cells. Epithelia form a continuous barrier between the outside environment and the internal medium while allowing the transport of ions, solutes and macromolecules between these compartments. The absorption of Na+ and the secretion of Cl− are major elements in the epithelial function.
Chloride ions penetrate into the epithelial cell through the basolateral surface with the help of a cotransporter, in the form of (Na+, K+, 2 Cl−) and leave it using the CFTR channels of the apical surface. [Al-Awqati, Q. (2002). Alternative treatment for secretory diarrhea revealed in a new class of CFTR inhibitors. J Clin Invest 110, 1599-1601].
Two types of pathologies can be associated with opposing CFTR channel dysfunctions.
Inhibition of the function is responsible for problems linked to cystic fibrosis. In this disease, due to genetic mutations, either the CFTR protein encoded is not delivered to the apical surface, or it cannot be activated, whence an impossibility for the chloride ions to leave the epithelial cell. This phenomenon induces absorption of sodium ions and leads to the thickening of mucus, obstructing the respiratory tract.
Inversely, overactivity of the CFTR channel causes diarrhoea. Excessive elimination of salts is accompanied by a loss of water, and therefore problems linked to dehydration. Overactivity of the CFTR channels can follow the presences of the toxins from bacteria such as Escherichia coli or Vibrio cholerae. 
The CFTR protein is a member of the superfamily of ABC (ATP-Binding Cassettes) transporters. It is made up of 1480 amino acids [Akabas, M. H. (2000). Cystic fibrosis transmembrane conductance regulator. Structure and function of an epithelial chloride channel. J Biol Chem 275, 3729-3732; Hume, J. R., Duan, D., Collier, M. L., Yamazaki, J., and Horowitz, B. (2000). Anion transport in heart. Physiol Rev 80, 31-81; Sheppard, D. N., and Welsh, M. J. (1999). Structure and function of the CFTR chloride channel. Physiol Rev 79, S23-45] comprising two homologous parts linked together by a cytoplasmic regulator domain (R). Each part has six transmembrane domains (M1 to M6 and M7 to M12) and a nucleotide binding domain (NBD-1 and NBD-2). There are two N-glycosylated sites between transmembrane domains M7 and M8.
The twelve transmembrane domains form a channel whose activity is determined by the phosphorylation of the R domain, as well as by the hydrolysis of ATP molecules bound in the NBDs. Anions and cations are present in the extracellular cone. The selectivity of this channel for anions seems mainly to be due to the presence of an arginine residue, Arg-352 (R352), at the tip of the cytoplasmic cone. The minimum diameter of this pore is approximately 5.3 Å. This size was determined using the largest anions which can penetrate into the cell. Transiently, however, the channel can dilate up to 13 Å in diameter.
The various CFTR channel activators known to date act in different ways. Among others, three modes of action can be mentioned:                those which act directly on the NBDs: genistein, which extends the opening of the channel; NS-004 or MPBs (substituted benzo[c]quinolizinium);        those which act by increasing the quantity of cyclic AMP needed to activate the R regulator domain: forskolin, which activates the cyclic AMP biosynthesis; milrinone, thought to act through its phosphodiesterase inhibiting action;        those which inhibit proteine phosphatase, enzymes which regulate the closing of the channel by dephosphorylation of the R domain, i.e. bromotetramisole or certain xanthines.        

As for the CFTR channel inhibitors, their mode of action usually consists in blocking the pore, thus keeping the ions from crossing through the channel [Hume, J. R., Duan, D., Collier, M. L., Yamazaki, J., and Horowitz, B. (2000). Anion transport in heart. Physiol Rev 80, 31-81]. Among others, we can mention carboxylic acids such as IAA-94 (indanyloxyacetic acid), DPC (diphenylamine-2-carboxylate) and NPPB (5-nitro-2-(3-phenylpropylamino)benzoate), DIDS (4,4′-diisothiocyanostylbene-2,2′-disulphonic acid) or sulphonylureas, including glibenclamine:

In high concentrations, these molecules inhibit the CFTR channels and are not specific to these channels. A 58-μM concentration of lonidamine is needed to inhibit 50% of the activity of the CFTR channel (IC50). These inhibitors also act on the other chloride channels and the potassium channels.
In 2002, Ma et al. reported a new class of inhibitors and new families of activators, both with very strong activity compared to those previously observed [Ma, T., Thiagarajah, J. R., Yang, H., Sonawane, N. D., Folli, C., Galietta, L. J., and Verkman, A. S. (2002a). Thiazolidinone CFTR inhibitor identified by high-throughput screening blocks cholera toxin-induced intestinal fluid secretion. J Clin Invest 110, 1651-1658; Ma, T., Vetrivel, L., Yang, H., Pedemonte, N., Zegarra-Moran, O., Galietta, L. J., and Verkman, A. S. (2002b). High-affinity activators of cystic fibrosis transmembrane conductance regulator (CFTR) chloride conductance identified by high-throughput screening. J Biol Chem 277, 37235-37241]:
